Phenylenediamine Urotensin-II receptor antagonists and CCR-9 antagonists

ABSTRACT

The present invention relates to urotensin II receptor antagonists, CCR-9 antagonists, pharmaceutical compositions containing them and their use.

FIELD OF THE INVENTION

The present invention relates to urotensin II receptor antagonists,pharmaceutical compositions containing them and their use.

BACKGROUND OF THE INVENTION

The integrated control of cardiovascular homeostasis is achieved througha combination of both direct neuronal control and systemic neurohormonalactivation. Although the resultant release of both contractile andrelaxant factors is normally under stringent regulation, an aberrationin this status quo can result in cardiohemodynamic dysfunction withpathological consequences.

The principal mammalian vasoactive factors that comprise thisneurohumoral axis are angiotensin-II, endothelin-1, and norepinephrine,all of which function via an interaction with specific G-protein coupledreceptors (GPCR). Urotensin-II, represents an important member of thisneurohumoral axis.

In the fish, this peptide has significant hemodynamic and endocrineactions in diverse end-organ systems and tissues:

-   both vascular and non-vascular (smooth muscle contraction) including    smooth muscle preparations from the gastrointestinal tract and    genitourinary tract. Both pressor and depressor activity has been    described upon systemic administration of exogenous peptide.-   osmoregulation effects which include the modulation of    transepithelial ion (Na⁺, Cl⁻) transport.

Although a diuretic effect has been described, such an effect ispostulated to be secondary to direct renovascular effects (elevatedGFR); urotensin-II influences prolactic secretion and exhibits alipolytic effect in fish (activating triacylglycerol lipase resulting inthe mobilization of non-esterified free fatty acids) (Person, et al.Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021; Conlon, et al. J. Exp.Zool. 1996, 275, 226); human Urotensin-II has been found to be anextremely potent and efficacious vasoconstrictor; exhibited sustainedcontractile activity that was extremely resistant to wash out; and haddetrimental effects on cardiac performance (myocardial contractility).Human Urotensin-II was assessed for contractile activity in therat-isolated aorta and was shown to be a very potent contractileagonist. Based on the in vitro pharmacology and in vivo hemodynamicprofile of human Urotensin-II, it plays a pathological role incardiovascular diseases characterized by excessive or abnormalvasoconstriction and myocardial dysfunction. (Ames et al. Nature 1990,401, 282.)

Compounds that antagonize the Urotensin-II receptor may be useful in thetreatment of congestive heart failure, stroke, ischemic heart disease(angina, myocardial ischemia), cardiac arrhythmia, hypertension(essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis),restenosis, atherosclerosis, dyslipidemia, asthma, neurogenicinflammation and metabolic vasculopathies all of which are characterizedby abnormal vasoconstriction and/or myocardial dysfunction. Urotensinantagonists may provide end organ protection in hypersensitive cohortsin addition to lowering blood pressure.

Since Urotensin-II and GPR 14 are both expressed within the mamamalianCNS (Ames et al. Nature 1999, 401, 282), they also may be useful in thetreatment of addiction, schizophrenia, cognitive disorders/Alzheimersdisease, impulsivity, anxiety, stress, depression, pain, migraine,neuromuscular function, Parkinsons, movement disorders, sleep-wakecycle, and incentive motivation.

Functional Urotensin-II receptors are expressed in rhabdomyosarcomascell lines and therefore may have oncological indications. Urotensin mayalso be implicated in various metabolic diseases such as diabetes and invarious gastrointestinal disorders, bone, cartilage, and joint disorders(e.g., arthritis and osteoporosis); and genito-urinary disorders.Therefore, these compounds may be useful for the prevention (treatment)of gastric reflux, gastric motility and ulcers, arthritis, osteoporosisand urinary incontinence.

CCR-9, a seven transmembrane, G-protein-coupled chemokine receptor wasrecently identified as the physiologic receptor forCCL25/thymus-expressed Chemokine (TECK). CCR-9 is mainly expressed inthymocytes and T lymphocytes from the small intestine and colon.CCL25/TECK is predominantly expressed in the thymus and small intestine.Studies have shown that CCR-9 mediates chemotaxis in response toCCL25/TECK is likely to play an important role in regulating thetrafficking of developing T cells within the thymus and be critical forthe development, homeostasis, and/or function of mucosal T lymphocytes.

It has been shown that CCR-9+ lymphocytes were markedly elevated inperipheral blood lymphocytes in patients with small bowl Crohn's orceliac disease. TECK expression is altered in an inflamed small bowel,being intensely expressed in a patchy distribution in crypt epithelialcells in proximity to lymphocytic infiltrates. Neutralization of TECKinhibits homing of CD8+ T cells to the IEL (intraepithelial lymphocyte)compartment. This directly demonstrates that CCL25 and CCR-9 function inrecruiting effector lymphocytes to the small intestinal epitheliumfollowing their activation in gut-associated lymphoid tissue (GALT).

Targeting CCL25/TECK and/or CCR-9 may provide a way to selectivelymodulate small-intestinal immune responses as suggested by the fact thatactivated CCR-9(+) CD8alphabeta(+) lymphocytes selectively localized tothe small-intestinal mucosa, and in vivo neutralization of CCL25/TECKreduced the ability of these cells to populate the small-intestinalepithelium These results demonstrate an important role for chemokines inthe localization of T lymphocytes to the small-intestinal mucosa.(Svensson et al., J. Clin. Invest., 2002, 110:1113-21)

CCR-9 receptor expression on human eosinophils from peripheral blood andbronchoalveolar lavage fluid after setmental antigen challenge wasreported recently (Liu et al, J Allergy Clin Immunol. 2003 September;112(3):556-62). CCR-9 was also found to selectively express on T-ALLCD4+ T cells and moderately express on T-CLL CDR+ T cells. CCL25/TECKselectively induced T-ALL CD4+ T cell chamotaxis and adhesion (Qiupinget al., Cancer Res. 2003 Oct. 1; 63(19):6469-77. Annels et al., Blood2003 Dec. 4 [Epub ahead of print]). A recent study also demonstrates anincrease in the expression of CCR-9 on peripheral blood gammadelta Tcells in individuals having HIV-1 infection (Poles et al., J Virol. 2003October; 77(19):10456-67).

SUMMARY OF THE INVENTION

In one aspect this invention provides for compounds and pharmaceuticalcompositions containing them.

In a second aspect, this invention provides for the use of thesecompounds as antagonists of urotensin II, and as inhibitors of urotensinII.

In another aspect, this invention provides for the use of thesecompounds for treating conditions associated with urotensin IIimbalance.

In yet another aspect, this invention provides for the use of thesecompounds for the treatment of congestive heart failure, stroke,ischemic heart disease (angina, myocardial ischemia), cardiacarrhythmia, hypertension (essential and pulmonary), renal disease (acuteand chronic renal failure/end stage renal disease) along with peripheralvascular disease (male erectile dysfunction, diabetic retinopathy,intermittent claudication/ischemic limb disease) and ischemic/hemorrhagestroke, COPD, restenosis, asthma, neurogenic inflammation, migraine,metabolic vasculopathies, bone/cartilage/joint disease, arthritis andother inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsisatherosclerosis, dyslipidemia, addiction, schizophrenia, cognitivedisorders/Alzheimers disease, impulsivity, anxiety, stress, depression,parkinsons, movement disorders, sleep-wake cycle, incentive motivation,pain, neuromuscular function, diabetes, gastric reflux, gastric motilitydisorders, ulcers and genitourinary diseases.

The urotensin antagonist may be administered alone or in conjunctionwith one or more other therapeutic agents, said agents being selectedfrom the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, A-II receptorantagonists, vasopeptidase inhibitors, diuretics, digoxin, and dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists.

In yet another aspect, the present invention provides compounds that areCCR-9 antagonists, the use of these compounds as CCR-9 antagonists andthe treatment of conditions associated with CCR-9 such as Crohn'sdisease, celiac disease and other forms of intestinal inflammation.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for compounds of Formula (I):

wherein:

-   R₁, R₂ and R₃ are independently selected from the group consisting    of hydrogen, halogen, C₁₋₆ alkyl, aryl, aralkyl, CN, CF₃ arene    sulfonyl, C₁₋₆ alkanesulfonyl, C₁₋₆ alkanecarbonyl, CONR₇R₈ and    CO₂R₉;-   X is N, CH₂, or O;-   Y is selected from the group consisting of SO₂, CO, CH₂SO₂, CH₂CO,    NHCO, OCO and NHSO₂;-   R₄ is selected from the group consisting of C₁₋₆ alkyl, aryl,    aralkyl, and heteroaryl;-   R₅ is the same as R₁ or Z-NR₇R₈ or R₄ and R₅ taken with N can form a    5 or 6 membered ring;-   Z is (CH₂)_(n) where n is 0-6;-   R₆ s selected from the group consisting of aryl, heteroaryl and    ZNR₇R₈;-   R₇ and R₈ are independently selected from the group consisting of    hydrogen, lower alkyl, aryl, and aralkyl or together with N form a    pyrrolidine, piperizine, piperidine or morpholine ring; and-   R₉ is selected from the group consisting of hydrogen, c₁₋₆ alkyl,    aryl, aralkyl, and the pharmaceutically acceptable salts thereof.

Preferably R₁, R₂ and R₃ are each methyl or R₁ and R₂ are methyl and R₃is hydrogen; X is N, Y is SO₂ and R₁ is 3,5-dichloro-2-hydroxybenzene.

In another embodiment, the CCR-9 antagonist compounds of the presentinvention have the general formula:

where E is NR¹¹, O, S, CR¹¹═CR¹², or CR¹¹═N, where R¹¹ and R¹² areindependently alkyl, aryl, hetero-aryl, halogen, hydroxy, alkoxy, orCONR₂ ¹¹;

-   D is NR¹⁰, O or S, where R¹⁰ is H, lower alkyl or aryl or R¹⁰ may    also be taken together with R¹⁶ or R¹³ to form a ring;-   Z is NR¹³ or CR¹³ ₂ where each R¹³ is independently H, lower alky,    aryl or heteroaryl;-   A is NR¹⁷ C═O or SO₂, where R¹⁷ is H, alkyl or aryl and may be taken    together with R¹⁴ to form a ring;-   when A is NR¹⁷, B is SO₂, CO₂ or CR¹⁸ ₂, where each R¹⁸ is    independently H, alkyl, aryl or heteroaryl;-   when A is C═O or SO₂, B is NR¹⁹, where R¹⁹ is H alkyl or aryl and    may be taken together with R¹² to form a ring;-   R¹³ and R¹⁴ are independently H, alkyl, aryl or heteroaryl; and-   R¹⁵ and R¹⁶ are independently H, alkyl, aryl, heteroaryl, halogen,    hydroxy, alkoxy or NR₂ ²¹, where R²¹ is H, alkyl, aryl or    heteroaryl, and the pharmaceutically acceptable salts thereof.

Presently preferred compounds are:

-   N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide-   3-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   2-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   1-(2-methoxyphenyl)-3-(2,4,6-trimnethyl-3-pyrrolidin-1-yl-phenyl)-urea-   4-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3-phenylaminosulfonyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide-   3-benzenesulfonylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide-   1-(4-chlorobenzenesulfonyl)-3-(2,4,6-trimnethyl-3-pyrrolidin-1-yl-phenyl)-urea-   N-(4-methyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   N-(2-methyl-5-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-biphenyl-2-carboxamide-   2-bromo-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   2-bromo-5-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   2-bromo-5-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   2,5-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenylaminosulfonyl)-thiophene-2-carboxylic    acid-   4-chloro-N-(2,4,6-trimethyl-3-morpholin-4-yl-phenyl)-benzenesulfonamide-   4-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   4′-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   2,3-dimethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   3-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   2-trifluoromethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   2-hydroxy-4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   4-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-phenyl-piperizin-1-yl)-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(piperidin-1-yl)-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2-methyl-5-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2-methyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-morpholin-4-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-methyl-piperidin-1-yl)-phenyl)-benzenesulfonamide-   2-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-methylpiperizin-1-yl)-phenyl)-benzenesulfonamide-   2,3-dimethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   3,5-dichloro-N-(3-diethylamino-2,4,6-trimethyl-phenyl)-2-hydroxy-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(4-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-methanesulfonylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(pyridin-3-ylamino)-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(4-methyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide-   3,5-dichloro-2-hydroxy-N-(3,4-dimethyl-2-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(4,5-dimethyl-2-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   3,5-dichloro-2-hydroxy-N-(3,5-dimethyl-2-pyrrolidin-1-yl-phenyl)-benzenesulfonamide-   N-(3-benzylamino-2,4,6-trimethyl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamide-   N-(2,4-dichloro-6-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenylaminosulfonyl)phenyl)-acetamide-   3,5-dichloro-N-(2-cyano-3-piperidin-1-yl-phenyl)-2-hydroxy-benzenesulfonamide-   2-methoxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide-   N-benzyl-N-(3-benzylamino-2,4,6-trimethyl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamide-   3,5-dichloro-N-(3-(1,3-dihydro-isoindol-2-yl)-2,4,6-trimethyl-phenyl)-2-hydroxy    benzenesulfonamide-   2-hydroxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide    tert-butyl    (2-(3,5-dichloro-2-hydroxybenzenesulfonylamino)-6-piperidin-1-yl-benzyl)-carbamate-   3,5-dichloro-N-(2-(dimethylamino)-ethyl)-2-hydroxy-N-(2,4,6-triethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide-   N-(2-aminomethyl-3-piperidin-1-yl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamide-   1-(2-(4-benzyl-piperazin-1-yl)-ethyl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea-   1-(2,4,6-trimethyl-3-(4-methyl-piperazin-1-yl)-phenyl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea.

The term “alkyl” as used herein, alone or in combination, refers toC₁-C₆ straight or branched, substituted or unsubstituted saturated chainradicals derived from saturated hydrocarbons by the removal of onehydrogen atom, unless the term alkyl is preceded by a C_(x)-C_(y)designation. Representative examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, andtert-butyl among others.

The term “aryl”, “arene” or “aromatic” as used herein alone or incombination, refers to a substituted or unsubstituted carbocyclicaromatic group having about 6 to 12 carbon atoms such as phenyl,naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or aheterocyclic aromatic group which is an aromatic ring containing atleast one endocyclic N, O or S atom such as furyl, thienyl, pyridyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinylpyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl,benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-napthridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. “Aralkyl” and“alkylaryl” employ the term “alkyl” as defined above. Rings may bemultiply substituted.

The term “aralkyl” as used herein, alone or in combination, refers to anaryl substituted alkyl radical, wherein the terms “alkyl” and aryl” areas defined above. Examples of suitable aralkyl radicals include, but arenot limited to, phenylnethyl, phenethyl, phenylhexyl, diphenylmethyl,pyridylmethyl, tetrazolyl methyl, furylnethyl, imidazolyl methyl,indolylmethyl, thienylpropyl and the like.

The term “heterocycle” as used herein, alone or in combination, refersto a non-aromatic 3- to 10-membered ring containing at least oneendocyclic N, O, or S atom. The heterocycle may be optionallyaryl-fused. The heterocycle may also optionally be substituted with atleast one substituent which is independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, amino, nitro,trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl,aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl among others.

The term “halogen” or “halo” as used herein, refers to fluorine,chlorine, bromine and iodine or fluoro, chloro, bromo and iodo,respectively.

The term “optical isomers” as used herein refers to compounds whichdiffer only in the stereochemistry of at least one atom, includingenantiomers, diastereomers and racemates.

Use of the above terms is meant to encompass substituted andunsubstituted moieties. Substitution may be by one or more groups suchas alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl,nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy,lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy,trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy,carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,alkylbeterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl or any of the substituents of the precedingparagraphs or any of those substituents either attached directly or bysuitable linkers. The linkers are typically short chains of 1-3 atomscontaining any combination of —C—,—C(O)—, —N—H—, —S—, —S(O)—, —O—,—C(O)O— or —S(O)O—. Rings may be substituted multiple times.

The terms “electron-withdrawing” or “electron-donating” refer to theability of a substituent to withdraw or donate electrons relative tothat of hydrogen if hydrogen occupied the same position in the molecule.These terms are well-understood by one skilled in the art and arediscussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18,incorporated herein by reference. Electron withdrawing groups includehalo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde,carboxyamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl andaryl lower alkanoyl among others. Electron donating groups include suchgroups as hydroxy, lower alkyl, amino, lower alkylamnino, di(loweralkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto,and disulfide among others. One skilled in the art will appreciate thatthe aforesaid substituents may have electron donating or electronwithdrawing properties under different chemical conditions. Moreover,the present invention contemplates any combination of substituentsselected from the above-identified groups.

The most preferred electron donating or electron withdrawingsubstituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl,aryloxy, carboxyl, carboxamide, cyano, sulfanyl, sulfoxide,heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, loweralkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto,mercaptoalkyl, alkylthio, carboxy lower alkyl, arylalkoxy,alkanoylamino, alkanoyl (lower alkyl) amino, lower alkylsufonylamino,arylsulfonylamino, alkylsulfonyl (lower alkyl) amino, arysulfonyl (loweralkyl) amino, lower alkylcarboxamide, di(lower alkyl) carboxaride,sulfonamide, lower alkylsulfonamide, di(lower alkyl sulfonamide, loweralkylsulfonyl, arylsulfonyl and alkyldithio.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts, awell as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

As used herein, the term “mammals” includes humans and other animals.

Compounds of the present invention may be synthesized according to thefollowing Schemes.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of soundmedical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66:1 et seq. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid. Representative acid addition salts include, but are notlimited to acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,dighiconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobtomic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylanmmonium, tetraethylammonium, methylainnonium,dimethylammonium, trimnethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgment. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection Or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal,intrastemal,subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompounds may also be complexed to ligands, such as antibodies, fortargeted delivery.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlledExamples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid, b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) hurnectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubillzing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes.

As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals which are dispersed in anaqueous medium Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed, Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. Prodrugs of the present invention may be rapidlytransformed in vivo to the parent compound of the above formula, forexample, by hydrolysis in blood A thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of theA. C. S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press (1987), hereby incorporated by reference.

Compounds of the present invention that are formed by in vivo conversionof a different compound that was administered to a mammal are intendedto be included within the scope of the present invention.

Compounds of the present invention may exist as stereoisomers whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The present invention contemplates various stereoisomersand mixtures thereof Stereoisomers include enantiomers anddiastereomers, and mixtures of enantiomers or iastereomers. Individualstereoisomers of compounds of the present invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of opticalenantiorners on chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer toth emselves a single dose.

Each dosage unit for oral administration contains suitably from 0.0001mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg, of a compound of Formula (I) or a pharmaceutically acceptable saltthereof calculated as the free acid. Each dosage unit for intranasaladministration contains suitably 1-400 mg and preferably 10 to 200 mgper person. A topical formulation contains suitably 0.01 to 1.0% of acompound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for parenteral administration is suitably about 0.01 mg/Kg to 40mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptablesalt thereof calculated as the free acid. The daily dosage regimen forintranasal administration and oral inhalation is suitably about 10 to500 mg/person. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit the desired activity.

These compounds may be used for the treatment of congestive heartfailure, stroke, ischemic heart disease (angina, myocardial ischemia),cardiac arrhythmia, hypertension (essential and pulmonary), renaldisease (acute and chronic renal failure/end stage renal disease) alongwith peripheral vascular disease (male erectile dysfunction, diabeticretinopathy, intermittent claudication/ischemic limb disease) andischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenicinflammation, migraine, metabolic vasculopathies, bone/cartilage/jointdisease, arthritis and other inflammatory diseases, fibrosis (e.g.pulmonary fibrosis), sepsis, atheroscloerosis, dyslipidemia, addiction,schizophrenia, cognitice disorders/Alzheimers disease, impulsivity,anxiety, stress, depression, pain, neuromuscular function, diabetes,gastric reflux, gastric motility disorders, ulcers and genitourinarydiseases.

The urotension antagonist may be administered alone or in conjunctionwith one or more other therapeutic agents, said agents being selectedfrom the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, A-II receptorantagonists, vasopeptidase inhibitors, duuretics, digoxin, and dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists.

The urotension related biological activity of the compounds of Formula(I) is demonstrated by the following tests:

-   1) Inhibition of Human [¹²⁵I]-Urotensin-II Binding to Urotensin-II    Receptor Binding of human [¹²⁵I]-urotensin-II to human urotensin-II    receptor (UTR) was done using cell membranes from either TE-671    rhabdomyosarcoma cells or CHO cells stably expressing recombinant    UTR, in a homogeneous Scintillation Proximity Assay (SPA).

The UTR cells membranes were pre-coupled overnight at 4° C. to WGA-PVTbeads (Amersham RPNQ0001) at a ratio of 5-25 μg membrane to 0.5 mgbeads/assay. Assay was performed in 96-well microtiter Optiplates(Packard 6005290) by mixing coupled beads and 0.1 nM [¹²⁵I U-II (2200Ci/mmol, NEN NEX379), in a total volume of 100 μl 20 mM HEPES, 5 mMMgCl₂, pH 7.4. Test compounds were diluted in DMSO and were put in theassay at a final concentration of 1% DMSO. Incubation was done for 3hours at 37° C. followed by reading in a TopCount scintillationmicroplate reader. Nonspecific binding was determined by adding 100 nMunlabeled human U-II (Phoenix Pharmaceuticals, 071-05) to the assaymixture. Analysis of the assay was performed using nonlinear leastsquare fitting.

1) Inhibition of Human Urotensin-II-induced Ca²⁺ mobilization in UTRCells:

The function of urotensin-II was determined by measuring ligand-inducedmobilization of intracellular Ca²⁺ in a FlexStation scanning fluorometer(Molecular Devices). UTR cells were plated overnight at 50,000cells/well in 96-well black/clear plates (Costar brand, Fisher07-200-588). Cells were labeled with fluo-4AM dye (Molecular Probes,F-14201) in Hank's balanced salt solution (HBSS), 20 mM HEPES, 25 mMprobenecid, pH 7.4, and then were washed with buffer. During the assay,cells were continuously monitored in the FlexStation and exposed to testcompounds at a final concentration of 0.1% DMSO, followed by theaddition of 1 nM human U-II. Fluorescence was read every 2 seconds for 2minutes. The excitation and emission wavelengths used were 485 run and525 nm. Inhibition of the urotensin-II-induced signal was calculatedusing a nonlinear least square fitting program. Activity for thecompounds of this invention is IC₅₀>0.5 mm (Example 30 IC₅₀=10 μM.

The CCR-9 antagonist activity of the compounds of the present inventionis shown by the following assay:

CCR9 FLIPR/FlexStation Assay Protocol

Calcium assay in FLIPR/FlexStation determines inhibitors of TECK inducedcalcium mobilization in CCR9-Flp-CHO cells that stably over expresshuman CCR-9 receptor. CCR-9-Flp-CHO cells are seeded at 20,000cells/well in a clear bottom, black wall 96-well plate (Greiner) one dayprior to assay. Cells are grown in a tissue culture incubator at 37° C.with 5% CO₂ for 18 to 24 hours.

Wash buffer and dye loading buffer are prepared fresh each time theassay is performed. Wash buffer is prepared according to the followingprotocol: 20 ml 10×HBSS, 4 ml 1 M HEPES, 176 ml sterile water, then add142 mg Probenecid to solution and pH to 7.4. This wash buffer contains1×HBSS, 20 mM HEPES and 2.5 mM probenecid. For one 96-well plate, dyeloading buffer is prepared as following: 11 ml wash buffer, 44 □lFluo-4/pluoronic acid mix (22 □l aliquot 2 mM Fluo-4 (Molecular Probes#F-14201, 50 μg/tube)+22 □l 20% pluronic F-127 (Molecular Devices,P-3000).

Cells are loaded with dye according to the protocol below:

-   1. Prepare wash buffer with 1×HBSS/HEPES at room temperature-   2. Prepare loading buffer (keep in dark)-   3. Aspirate culture media-   4. Add 100 μl dye loading buffer to each well-   5. Incubate at 37° C. for 1 hr-   6. Aspirate loading buffer-   7. Wash with 200 μl per well ×2-   8. Add 100 μl wash buffer per well-   9. Ready to assay plate with FLIPR or FlexStation

10 mM stock compounds in DMSO are prepared Compounds are diluted in washbuffer to make 8 point series dilutions containing same concentration ofDMSO (less than 0.3%). Compounds are tested in duplicate wells for eachpoint. Ligand rhTECK was diluted to 5× of its EC50 with wash buffercontaining 0.5% BSA. Appropriate amount of 5× ligand is added to eachwell. Data is analyzed using GraphPad Prism software to calculate IC50value of antagonist activity for each compound.

The following Examples are illustrative but not limiting of the presentinvention:

EXAMPLE 1N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide

1). 2,4,6-Trimethyl-3-pyrrolidin-1-yl-phenylamine (2). To a solution of2,4,6-trimethyl-1,3-phenylenediamine (15.0 g, 99.8 mmol) in anhydrousDMF (300 mL) were sequentially added potassium carbonate (30.4 g, 219.7mmol) and 1,4-dibromobutane (11.9 mL, 99.8 mmol). The reaction wasstirred overnight and then partitioned between water and ethyl acetate.The organic layer was washed with brine, dried (MgSO₄) and concentrated.The residue was chromatographed eluting with hexanes:ethyl acetate(20:1) to give the desired product (10.8 g, 53%).

The titled compound was synthesized as shown in scheme 2 using 2 to givea white solid (ESI [M+H⁺])=315.21.

Examples 2-97 (Table 1) were Synthesized in Similar Fashion.

Ex- am- physical ple structure name description M + H 1

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamidewhite solid 315.21 2

3-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowfoam 323.24 3

2-phenyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-acetamide 323.27 4

2-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowsolid 343.25 5

2-benzyloxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide brownfoam 415.27 6

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamideyellow foam 385.32 7

4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide lightbrown solid 323.26 8

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-cyclopentanecarboxamidepale yellow solid 301.25 9

4-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 379.12 10

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-acetamide off-white solid247.26 11

2-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamideoff-white solid 323.28 12

N-(4-methyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide dark tansolid 357.29 13

N-(2-methyl-5-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide white solid357.32 14

N-(3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide yellow solid 343.2615

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellow solid309.23 16

2,2-diphenyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-acetamidewhite crystal 399.28 17

N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-biphenyl-2-carboxamideoff-white solid 399.28 18

5-dimethylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-naphthalene-1-sulfonamdielight yellow foam 438.24 19

N-(2-methyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide white solid357.26 20

2-bromo-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide whitesolid 387.28 21

2,3-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidelight yellow solid 377.2 22

2-bromo-5-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidewhite solid 23

2-bromo-5-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamideyellow solid 24

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-quinoline-8-sulfonamidelight yellow foam 396.17 25

methyl3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenylaminosulfonyl)-thiophene-2-carboxylateyellowish solid 409.17 26

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide whitesolid 345.22 27

2,5-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite solid 413.15 28

3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenylaminosulfonyl)-thiophene-2-carboxylicacid yellowish solid 395.18 29

2-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 379.14 30

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-naphthalene-1-sulfonamideyellow solid 395.25 31

N-(biphenyl-2-yl)-quinoxaline-6-carboxamide yellow solid 326.09 32

2-bromo-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite solid 423.14 33

2-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 359.17 34

3-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight yellow solid 359.17 35

2-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide whitesolid 324.28 36

3-trifluoromethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 427.13M − H 37

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-sulfonamidelight yellow foam 421.18 38

2-bromo-3-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidecolorless film 401.1 39

2-bromo-5-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidewhite foam 421.12 40

2-fluoro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow powder 363.18 41

3,4-dimethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidetan solid 405.27 42

2-trifluoromethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelow crystalline so 423.11 43

methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-phthalamate whitesolid 367.29 44

2-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide brownfoam 339.34 45

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-4-carboxamidewhite solid 385.21 46

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-phenylmethanesulfonamideyellow foam 359.23 47

2-chloro-5-trifluoromethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidetan solid 447.19 48

5-methoxy-2-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide49

2,5-dimethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideoil 405.27 50

2-methoxy-4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight yellow foam 51

2,3-dimethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidebrown foam 369.29 52

2,6-dimethoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidelight brown solid 369.29 53

2-methoxy-5-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight brown solid 389.22 54

5-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-naphthalene-2-sulfonamidetan solid 429.22 55

4-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite solid 375.2 56

4-fluoro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide363.14 57

3,4-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight orange solid 413.25 58

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-4-sulfonamideoff-white solid 421.23 59

C-(3-chlorophenyl)-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-methanesulfonamideyellow foam 393.18 60

3-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowfoam 343.29 61

2,6-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidebrown solid 377.14 62

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-naphthalene-2-carboxamideoff-white solid 359.26 63

2-trifluoromethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamideyellow solid 377.21 64

3-fluoro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 363.07 65

4-tert-butyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidetan crystals 401.25 66

3-phenyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamidebrown solid 391.16 67

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-naphthalene-1-carboxamideoff-white foam 359.27 68

2-phenyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-ethenesulfonamidelight yellow foam 69

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideoff-white solid 429.12 70

4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight brown solid 359.11 71

4-(4-dimethylamino-phenylazo)-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide492.15 72

N-(4-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)aminosulfonyl)-phenyl-acetamide402.15 73

3-bromo-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamideyellowish solid 393.07 74

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-phthalamic acid yellowishsolid 353.14 75

3-bromo-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide whitesolid 387.21 76

N-(4-(2-methyl-pyrimidin-4-yl)-phenyl)-biphenyl-2-carboxamide 77

N-(3-methyl-cinnolin-5-yl)-biphenyl-2-carboxamide 78

N-(4-methyl-6-methylthio-(1,3,5)-triazin-2-yl)-biphenyl-2-carboxamide 79

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(piperidin-1-yl)-phenyl)-benzenesulfonamidelight yellow foam 442.99 80

4-((2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-aminosulfonyl)-benzoicacid pale yellow solid 389.09 81

2,4,6-trimethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideoff-white solid 387.22 82

3,5-dimethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight orange solid 373.24 83

4-butyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidetan solid 401.21 84

4-propyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidetan solid 387.21 85

3,5-dichloro-2-hydroxy-N-(2-methyl-5-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 401.15 86

3,5-dichloro-2-hydroxy-N-(2-methyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight pink solid 401.14 87

4-ethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideoff-white solid 373.13 88

4-isopropyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidepale orange solid 387.21 89

N-(3-hydroxy-pyridin-2-yl)-4-methoxy-3-pyrrolidin-1-yl-benzamide beigesolid 314.36 90

4′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamideyellow solid 91

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-3-carboxamidecolorless oil 92

5-bromo-2-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite solid 93

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-methylpiperidin-1-yl)-phenyl)-benzenesulfonamideyellow solid 457.04 94

3,5-dichloro-2-hydroxy-N-(3-amino-2,4,6-trimethyl-phenyl)-benzenesulfonamidetan solid 375.04 95

2,3-dimethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidewhite foam 337.28 96

3,5-dichloro-2-hydroxy-N-(4-pyrrolidin-1-yl-cyclohexyl)-benzenesulfonamidewhite solid 379.17 97

3,5-dichloro-N-(3-diethylamino-2,4,6-trimethyl-phenyl)-2-hydroxy-benzenesulfonamideyellow solid 431.2

EXAMPLE 973,5-dichloro-N-(3-diethylamino-2,4,6-trimethyl-phenyl)-2-hydroxy-benzenesulfonamide

1) Diethylamino-2,4,6-trimethyl-phenylamine (5). Compound 5 wassynthesized as shown in Scheme 1 using a literature procedure (Wu, et.al. J Med. Chem. 1999, 42, 4485-4499).

2) The title compound was synthesized by coupling of 5 with3,5-dichloro-2-hydroxybenzenesulfonyl chloride as shown in Scheme 2 for21 to give a yellow solid (ESI [M+H⁺]=431.2).

EXAMPLE 983,5-dichloro-2-hydroxy-N-(4-pyrrolidin-1-yl-phenyl)-benzenesulfonamide

1) 1-(4-Nitrophenyl)-pyrrolidine (7). To a solution of 4-nitroaniline (1g, 7.2 mmol) in DMF (20 mL) was added sodium hydride (60% in mineraloil, 0.579 g, 14.4 mmol). The mixture was placed under nitrogenatmosphere and stirred for 5 minutes before the addition of1,4-Dibromobutane (0.86 mL, 7.2 mmol). The resulting mixture was stirredfor additional 15 min and then extracted with ethyl acetate (30 mL, 20mL) and washed with water and brine (15 mL each). The ethyl acetateextracts were combined and dried (MgSO₄), the solids filtered and thefiltrate concentrated to give the crude 7 as a yellow solid.

2) 4-(Pyrrolidin-1-yl)-phenylamine (8). To a solution of 7 in ethanol(20 mL) was added 10 wt % Pd on carbon (Degussa) (25 mg, 23 □mol).Glacial acetic acid (2-3 drops) was added to the reaction. The reactionwas placed under a H₂ atmosphere and stirred for 16 hours, after whichthe reaction mixture was filtered through a pad of celite. The filtratewas evaporated, and the residue then dissolved in ethyl acetate (20 mL)and washed with 2N HCl (aq. 15 mL). The aqueous phase was isolated andthen basified by the addition of 2N NaOH (aq. 20 mL). The aqueous layerwas extracted with ethyl acetate (20 mL×2). The ethyl acetate extractswere dried over anhydrous magnesium sulfate, filtered, and evaporated togive crude 8 as a yellow oil (642 mg, 55% for 2 steps).

3) The title compound was synthesized in the same fashion as for 21(Scheme 2) using 8 and 3,5-dichloro-2-hydroxybenzenesulfonyl chloride asa yellow solid (ESI M+H=387.18).

EXAMPLE 1194-Chloro-N-(2,4,6-trimethyl-3-(4-methyl-piperizin-1-yl)-phenyl)-benzenesulfonamide

1). 2,4,6-Trimethyl-3-(4-methyl-piperizin-1-yl)-phenylamine (11). To asolution of 1 (1.5 g, 10 mmol) in anhydrous DMF (20 mL) weresequentially added mechlorethamine hydrochloride (1.93 g, 10 mmol) andcesium carbonate (10.4 g, 32 mmol). The resulting mixture was heated for6 hours at 120° C. under nitrogen and was worked up as usual. Columnchromatography eluting with EtOAc:methanol (10:1) then 100% methanolgave 900 mg of 11.

2) The title compound was synthesized following the protocol shown inScheme 2 using 11 and 4-chlorobenzenesulfonyl chloride as a yellow solid(ESI M+H=408.21). The compounds of Examples 99-118 and 120-128 areprepared by the procedures of Examples 98 and 119.

98

3,5-dichloro-2-hydroxy-N-(4-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 387.18 99

3,5-dichloro-2-hydroxy-N-(2-pyrrolidin-1-yl-phenyl)-benzenesulfonamidebrown solid 387.13 100

4-bromo-2-trifluoromethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamidewhite solid 521.15 101

3,5-dichloro-2-hydroxy-N-(4-methyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidelight brown solid 401.08 102

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamidelight brown foam 393.14 103

2-cyano-N-(2,4,6-trimethyl-3-pyrroiidin-1-yl-phenyl)-benzenesulfonamidebrownish solid 370.05 104

3-cyano-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidebrownish solid 370.19 105

4-cyano-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellowish solid 370.17 106

3,5-dichloro-2-hydroxy-N-(3,4-dimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidepink solid 415.10 107

3,5-dichloro-2-hydroxy-N-(4,5-dimethyl-2-pyrrolidin-1-yl-phenyl)-benzenesulfonamide415.05 108

3,5-dichloro-2-hydroxy-N-(3,5-dimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideorange solid 415.17 109

N-benzyl-3,5-dichloro-N-(2-dimethylamino-ethyl)-2-hydroxy-benzenesulfonamidewhite solid 403.17 110

3,5-dichloro-N-(2-cyano-3-piperidin-1-yl-phenyl)-2-hydroxy-benzenesulfonamideoff-white solid 423.97 111

3,5-dichloro-N-(3-(1,3-dihydro-isoindol-2-yl)-2,4,6-trimethyl-phenyl)-2-hydroxy-benzenesulfonamidetan solid 112

4-benzyloxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide whitesolid 113

3-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowsolid 114

4-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowsolid 115

2-hydroxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperlidin-1-yl-phenyl)-benzenesulfonamidebrownish solid 402.24 116

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethylphenyl)-benzenesulfonamidelight yellow foam 358.17M − H Ex- am- physical ple Structure namedescription M + H 117

N-(2,4,6-trimethyl-3-morpholin-4-yl-phenyl)-biphenyl-2-carboxamideoff-white solid 401.26 118

4-chloro-N-(2,4,6-trimethyl-3-morpholin-4-yl-phenyl)- brownish solid395.14 119

4-chloro-N-(2,4,6-trimethyl-3-(4-methyl-piperizin-1-yl)-phenyl)-benzenesulfonamideyellow solid 408.21 120

N-(2,4,6-trimethyl-3-(4-methyl-piperizin-1-yl)-phenyl)-biphenyl-2-carboxamideyellowish solid 414.36 121

3-methyl-N-(2,4,6-trimethyl-3-(4-phenyl-piperizin-1-yl)-phenyl)-benzenesulfonamideoff-white solid 450.25 122

4-tert-butyl-N-(2,4,6-trimethyl-3-(4-methyl-piperizin-1-yl)-phenyl)-benzenesulfonamidebrownish solid 429.18 123

3-chloro-N-(2,4,6-trimethyl-3-(4-methyl-piperizin-1-yl)-phenyl)-benzamidewhite solid 371.16 124

4-tert-butyl-N-(2,4,6-trimethyl-3-(4-phenyl-piperizin-1-yl)-phenyl)-benzenesulfonamidewhite solid 492.26 125

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-phenyl-piperizin-1-yl)-phenyl)-benzenesulfonamideyellowish solid 520.06 126

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-morpholin-4-yl-phenyl)-benzenesulfonamidepink foam 127

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-methylpiperidin-1-yl)-phenyl)-benzenesulfonamideyellow solid 457.04 128

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(4-methylpiperizin-1-yl)-phenyl)-benzenesulfonamideyellow solid 458.1

EXAMPLE 1294-tert-Butyl-N-(3-(3-dimethylamino-2,2-dimethyl-propylamino)-2,4,6-trimethyl-phenyl)-benzenesulfonamide1)N-(3-Dimethylamino-2,2-dimethyl-propyl)-2,4,6-trimnethyl-benzene-1,3-diamine(15)

Sodium tert-butoxide (288.33 mg, 3 mmol), Pd₂(dba)₃, (104 mg, 0.1 mmol),and BINAP (125 mg, 0.2 mmol) were mixed in a sealed tube and the tubewas purged with N₂. 3-Bromo-2,4,6-trimethyl-aniline (428.22 mg, 2 mmol)and 2,2-N¹,N¹-tetramethyl-propane-1,3-diamine (0.413 ml, 2.6 mmol) andtoluene (5 mL) were then sequentially added to the tube. The mixture wasdegassed three times and filled with N₂, sealed, and heated for 36 hoursat 100° C. The tube was cooled to room temperature and worked up asusual. The crude products were purified by loaded into columnchromatography (florisil) eluting with hexanes: EtOAc (3:1 to 1:2 ratio)to give 329 mg 15.

2). The titled compound was synthesized as shown in Scheme 2 using 15and 4-tert-butylbenzenesulfonyl chloride as a yellow solid (ESI[M+H⁺]=460.11).

The compounds of Examples 130-132 are prepared by the procedure ofExample 129.

physical Example Structure name description M + H 130

3,5-dichloro-2-hydroxy-N-(3-(3-dimethylamino-2,2-dimethylpropylamino)-2,4,6-trimethyl-phenyl)-benzenesulfonamideyellowish solid 488.21 131

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(pyridin-3-ylamino)-phenyl)-benzenesulfonamidewhite solid 452.07 132

3,5-dichloro-2-hydroxy-N-(2,4,6-trimethyl-3-(pyridin-3-ylamino)-phenyl)-benzenesulfonamideyellowish solid 452.12

EXAMPLE 133 AND 134N-(3-Benzylamino-2,4,6-trimethyl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamideandN-benzyl-N-(3-benzylamino-2,4,6-trimethyl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamide

1) N-Benzyl-2,4,6-trimethyl-benzene-1,3-diamine (16) andN,N′-dibenzyl-2,4,6-trimethyl-benzene-1,3-diamine (17)

To a solution of 2,4,6-trimethyl-1,3-phenylenediamine (2.0 g, 13.3 mmol)in anhydrous DMF (40 mL) were sequentially added potassium carbonate(2.8 g, 20.0 mmol) and benzyl bromide (1.6 mL, 13.3 mmol). The reactionwas stirred overnight and partitioned between water and ethyl acetate.The organic layer was washed with brine, dried (MgSO₄), the solids werefiltered off and the filtrate concentrated The residue waschromatographed eluting with hexanes:ethyl acetate (80:1-40:1-20:1) togive a 1:1 mixture of 16 and 17.

2). The title compounds were synthesized as shown in Scheme 2 using3,5-dichloro-2-hydroxy-benzenesulfonyl chloride and 16, 17,respectively, as white foams. ESI [M+H⁺]=465.04 (example 133);M−H=553.075 for (example 134).

EXAMPLE 135(2-chloro-benzyl)-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-amine 18

To a solution of aniline 1 (121 mg, 0.59 mmol) in DMF (4.9 mL) was addedtriethylamine (0.141 mL, 1.00 mmol). 2-Chlorobenzyl chloride (0.08 mL,0.63 mmol) was then added, and the reaction was heated at 80° C. for 22hrs. After cooling the reaction mixture to room temperature, the mixturewas extracted with ethyl acetate (20 mL×2) and washed with water andbrine (10 mL each). The ethyl acetate extracts were dried over anhydrousmagnesium sulfate, filtered, and evaporated to give the crude product.Column chromatography on silica (15:1 to 7:1 hexanes/ethyl acetate) gavethe product (R_(f)≈0.6 in 10/1 hexanes/ethyl acetate) as a yellow oil(14 mg, 7%). ESI [M+H⁺]=329.1.

EXAMPLE 136Biphenyl-2-ylmethyl-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-amine(19)

The title compound was synthesized in the same manner as for example 135as a yellow oil. ESI [M+H⁺]=371.19.

EXAMPLE 1374-Methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamide

To a solution of the aryl bromide 22 (example 22) (106 mg, 0.25 mmol) intoluene (2.4 mL) was added saturated aqueous sodium bicarbonate solution(1.0 ml). The mixture was placed under a nitrogen atmosphere followed bythe addition of a solution of phenyl boronic acid (43 mg, 0.35 mmol) inEtOH (1.8 mL). Pd(Ph₃P)₄ (19 mg, 0.02 mmol) was added, and the reactionwas then heated at 80° C. for 70 hrs. After cooling the reaction mixtureto room temperature, the mixture was extracted with ethyl acetate (30mL, 20 mL) and washed with water and brine (15 mL each). The ethylacetate extracts were dried over anhydrous magnesium sulfate, filtered,and evaporated to give the crude product. Column chromatography onsilica (5:1 to 4:1 hexanes/ethyl acetate) gave the product (R_(f)=0.4 in3/1 hexanes/ethyl acetate) as a white solid (46 mg, 44%). ESI[M+H⁺]=415.21.

The compounds of Examples 138-148 are prepared by the procedure ofExample 137.

physical Example Structure name description M + H 137

4-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamidewhite solid 415.21 138

4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamidewhite solid 399.24 139

2′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamideyellow solid 140

6-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamidewhite solid 299.26 141

3′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamideyellow solid 399.29 142

4′-chloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamidewhite solid 419.2 143

4-trifluoromethyl-N-(2,4,6-trimethyl-3-(1,3-dihydro-isoindol-2-yl)-phenyl)-biphenyl-2-carboxamideyellow solid 501.25 144

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamidewhite solid 453.19 145

4-methoxy-3′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-carboxamideyellow solid 146

N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-2-sulfonamidelight yellow foam 421.18 147

4-methoxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-3-sulfonamidewhite solid 451.21 148

4-methoxy-2′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-3-sulfonamideyellow oil/gel 465.25

EXAMPLE 1492-Phenyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-ethanesulfonamide

To a solution of Example 68 (0.20 g, 0.55 mmol) in EtOH (8 mL) was addedPd (10% on carbon, degussa, 0.20 g) and 10 drops of AcOH. This mixturewas then sealed with a septum and put under vacuum for 1 minute beforesubjected to a H₂ atmosphere overnight at room temperature. TLCindicated the reaction did not go to completion. After filtration toremove the catalyst, the filtrate was concentrated and the desiredproduct was separated by silica gel chromatography (10% to 25% EtOAc inhexanes) to yield 0.070 g of the title compound as a yellow solid. ESI[M+H⁺]=373.16.

EXAMPLE 1502-Methoxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide(32)

1) 2-Methoxy-3,5-dimethyl-benzenesulfonyl chloride (29). To a solutionof 2,4-dimethylanisole (4.18 g, 30 mmol) in anhydrous 1,2-dichloroethane(45 mL) at 0° C. and under N₂ were added dropwise ClSO₃H (2.55 mL, 38mmol) and PCl₅ (6.7 g, 31.5 mmol) in portions. The mixture was stirredovernight at room temperature and poured into ice water with vigorousstirring. The aqueous mixture was extracted with dichloromethane and theorganic layer was washed with brine two times and dried over NaSO₄. Thesolids were filtered off and the filtrate was concentrated in a rotavapto afford 29 (4.5 g).

2) The title compounds was synthesized as usual (Scheme 2) using 29 andthe phenylenediamine 30 as a white solid ESI [M+H⁺]=417.22.

EXAMPLE 151 (TBC6274).3,5-Dichloro-2-methoxy-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide(31)

The title compound was synthesized in the same manner as for example 150as a light yellow foam.

EXAMPLE 152N-(2-(Dimethylamino)-ethyl)-2-methoxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide(34)

To a solution of 32 (103 mg, 0.25 mmol) in anhydrous DMF (5 mL) wasadded NaH (60% dispersion in mineral oil, 22 mg, 0.54 mmol). The mixturewas stirred for 10 min at room temperature before the addition of2-(dimethylamino)-ethyl chloride hydrochloride (39.2 mg, 0.27 mmol). Theresulting mixture was heated overnight at 85° C. After a usual workup,the residue was loaded onto column (Florisil) and the column eluted withEtOAc/CH₃OH (10:1) to give 80 mg of the title compound as an off-whitesolid ESI [M+H⁺]=488.27.

EXAMPLE 1533,5-Dichloro-N-(2-(dimethylamino)-ethyl)-2-methoxy-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide(33)

The title compound was synthesized in the same manner as for Example 152as light yellow foam. ESI [M+H⁺]=528.28.

EXAMPLE 1542-Hydroxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide(35)

Under a nitrogen atomersphere, 32 (88 mg, 0.21 mmol) was dissolved indichloromethane (6 mL) followed by the addition of BBr₃ (0.2 mL, 2.1mmol). The reaction was stirred overnight at room temperature and thenquenched with ice. The mixture was partitioned between EtOAc and waterand the organic layer was separated, washed with brine, and dried overNa₂SO₄. The solids were filtered off and the filtrate was concentratedin a rotavap to give 70 mg of the title compound as a brownish solid ESI[M+H⁺]=402.24.

The compounds of Examples 155-160 are prepared by the procedure ofExample 154.

physical Example structure name description M + H 154

2-hydroxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamidebrownish solid 402.24 155

3,5-dichloro-N-(2-(dimethylamino)-ethyl)-2-hydroxy-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamideyellow solid 514.25 156

N-(2-(dimethylamino)-ethyl)-2-hydroxy-3,5-dimethyl-N-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-benzenesulfonamide157

4-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-3-sulfonamidewhite solid 435.0938M − 1 158

4-hydroxy-2′-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-biphenyl-3-sulfonamidecolorless film 449.1259M − 1 159

2-hydroxy-4-methyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite solid 375.14 160

4-hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidewhite foam

EXAMPLE 1612-Amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzesulfonamide(39)

The title compound was synthesized in the same manner as for Example 149from 38 as a light yellow foam. ESI [M+H⁺]=360.08.

The compounds of Examples 162-165 are prepared by the procedure ofExample 161.

physical Example structure name description M + H 161

2-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzesulfonamidelight yellow foam 360.08 162

4-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow foam 163

4-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowsolid 164

2-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide whitesolid 324.28 165

3-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide yellowsolid 324.29

EXAMPLE 1664-Hydroxy-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide

The title compound, a yellow solid, was synthesized in the same manneras for Example 149 using Example 111 as the substrate for catalytichydrogenation.

EXAMPLE 1672-Amino-3,5-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide(40)

To a solution of 39 (0.12 g, 0.32 mmol) in acetic acid (4.0 mL) at 0° C.was added sulfuryl chloride (0.092 g, 0.68 mmol) dropwise. After beingstirred at room temperature for 2 h, the reaction mixture was quenchedwith cold saturated (aq.) NaHCO₃ and was extracted with EtOAc (70 mL).The organic layer was washed with sat. NaHCO₃, H₂O, and brine before itwas dried (MgSO₄) and evaporated to dryness. The resulting crude productwas chromatographed eluting with 10% to 25% EtOAc in hexanes to yieldthe title compounds as a light-yellow solid (0.11 g, 79%, ESI[M+H⁺]=428.13).

EXAMPLE 1684-Amino-3,5-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide

The title compound was synthesized in the same manner as for Example 167using Example 163 as the substrate for chlorination reaction. It was atan solid ESI [M+H⁺]=428.11.

EXAMPLE 1693,5-Dichloro-2-methanesulfonylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide(42)

To a solution of 40 (69 mg, 0.16 mmol) in DMF at 0° C. was added NaH(60% in mineral oil, 14 mg, 0.35 mmol). The mixture was stirred for 10min at 0° C. before the addition of methanesulfonyl chloride (22 mg,0.19 mmol). The resulting mixture was then stirred at room temperatureovernight. The reaction was quenched with a few drops of dilute HCl andthen diluted with EtOAc (60 mL). The organic layer was washed with water(2×30 mL) and brine (30 mL) and the volatiles were removed byevaporation on a rotavap. The residue was purified on a silica gelcolumn (15% to 30% EtOAc in hexanes) to yield the title compounds as anoff-white solid (10 mg ESI [M+H⁺]=506.12).

EXAMPLE 170N-(2,4-Dichloro-6-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenylaminosulfonyl)phenyl)-acetamide(41)

The title compound was synthesized in the same manner as for Example 169using acetyl chloride instead of methanesulfonyl chloride. It wasobtained as an off-white solid (ESI [M−H⁺]=468.22).

EXAMPLE 171 Tert-Butyl(2-(3,5-dichloro-2-hydroxybenzene-sulfonylamino)-6-piperidin-1-yl-benzyl)-carbamate(47)

1) 2-Amino-6-piperidin-1-yl-benzonitrile (44). A solution of2-amino-6-fluoro-benzonitrile (844 mg, 6.2 mmol) in piperidine (5 mL)was heated overnight at 80° C. After usual workup, the residue wasloaded into column (silica gel) and eluted with hexanes:EtOAc (5:1) togive 450 mg of 44.

2) 2-Amino-6-piperidin-1-yl-benzylamine (44a). To a solution of 44 (260mg, 1.29 mmol) in anhydrous THF (6 mL) was added lithium aluminumhydride (1 M in THF, 6 mL, 6 mmol). The mixture was heated overnight at75° C. The reaction was allowed to cool to room temperature and quenchedwith Na₂SO₄.10H₂O and stirred for 30 min. The solids were filtered off,the filtrate was concentrated on a rotavap to afford 44a (270 mg).

3) tert-Butyl (2-amino-6-piperidin-1-yl-benzyl)-carbamate (45). To asolution of 44a (300 mg, 1.46 mmol) in anhydrous THF (8 mL) was addedBoc₂O (351 mg, 1.61 mmol) and the mixture was stirred overnight at roomtemperature. After usual workup, the residue was loaded into column(silica gel) and eluted with hexanes: EtOAc (7:1) to give 45 (160 mg).

4) The title compound was synthesized according to the protocol shown inScheme 2 using 45 and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride(46). It was an off-white solid (ESI ([M+H⁺]=530.11).

EXAMPLE 172N-(2-Aminomethyl-3-piperidin-1-yl-phenyl)-3,5-dichloro-2-hydroxy-benzenesulfonamide(48)

To a solution of 47 (75 mg) in dichloromethane (5 mL) was added TFA (0.5mL). The solution was stirred overnight. Followed by usual workup. Thetitle compound was obtained as an off-white solid (35 mg).

EXAMPLE 1732-Aminomethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide

The title compound was synthesized from the corresponding nitrile(Example 103) using the procedure as shown for 44a.

The compounds of Examples 174-175 are prepared by the procebure ofExample 173.

physical Example structure name description M + H 173

2-aminomethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamidegreen solid 373.95 174

3-aminomethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 374.16 175

4-aminomethyl-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamideyellow solid 374.13

EXAMPLE 1763-Phenylaminosulfonyl-N-(2,4,6-trimnethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide(53)

The title compound was synthesized according to a literature sequence(Wu, et. al. J. Med. Chem. 1999, 42, 4485-4499) of sulfonamidecoupling/MOM protection/amide coupling/MOM deprotection (Scheme 4) as ayellowish solid ESI [M+H⁺]=470.2.

EXAMPLE 1773-Benzenesulfonylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-thiophene-2-carboxamide(58)

The title compound was synthesized according to the same reactionsequence (Scheme 4) as for Example 176, except that coupling partnerswere methyl 3-amino-thiophene-2-carboxylate (54) and benzenesulfonylchloride. It was an amber solid ESI [M+H⁺]=470.15.

EXAMPLE 1781-(2-Methoxyphenyl)-3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-urea

A solution of 2 (0.25 g, 1.22 mmol) and 2-methoxyphenyl isocyanate (0.18g, 1.22 mmol) in toluene (5 mL) was heated at 80° C. overnight. Themixture was allowed to cool to room temperature and then diluted withEtOAc. The organic layer was washed with water (50 mL) and brine (50 mL)before it was dried (MgSO₄) and concentrated on a rotavap. The residuewas chromatographed on silica gel to give the title compound (0.11 g) asa solid. ESI [M+H⁺]=354.22.

The compounds of Examples 179-184 are prepared by the procedure ofExample 178.

physical Example structure name description M + H 178

1-(2-methoxyphenyl)-3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-urea354.22 179

1-(4-chlorophenyl)-3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-urea358.17 180

1-(4-chlorobenzenesulfonyl)-3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-ureayellow solid 421.23 181

1-(biphenyl-2-yl)-3-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-ureayellow foam 400.29 182

1-(2-(4-benzyl-piperazin-1-yl)-ethyl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea183

1-(2-(1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea184

1-(2,4,6-trimethyl-3-(4-methyl-piperazin-1-yl)-phenyl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea

EXAMPLE 1821-(2-(4-benzyl-piperazin-1-yl)-ethyl)-3-(2,4,6-trimethyl-3-piperidin-1-yl-phenyl)-urea

To a solution of 2,4,6-trimethyl-3-piperazin-1-yl-phenylamine (0.2 g,0.92 mmol) and Hunig's base (0.7 mL, 4.0 mmol) in anhydrous1,2-dichloroethane (3 mL) at 0° C. was added triphosgene (0.1 g, 0.35mmol). The mixture was stirred at 0° C. for 30 minutes before theaddition of a solution of 2-(4-benzyl-piperazin-1-yl)-ethylamine (0.2 g,0.92 mmol) in 1,2-dichloroethane (2 mL). The reaction was stirredovernight and partitioned between water and methylene chloride. Theorganic layer was washed with brine, dried (MgSO₄) and concentrated. Theresidue was chromatographed with florisil, eluting with a mixture ofhexanes and ethyl acetate in the ratio of 2:1 to 100% ethyl acetate, andthen to a mixture of ethyl acetate and MeOH (30:1) to give the titlecompound as a white foam (0.27 g, 64% yield).

EXAMPLE 185N-benzyl-2-benzyloxy-3,5-dichloro-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzenesulfonamide

To a solution of Example 69 (0.10 g, 0.23 mmol) in anhydrous DMF (3 mL)were sequentially added benzyl bromide (0.039 g, 0.23 mmol) and K₂CO₃(0.032 g, 0.23 mmol). The mixture was stirred at room temperatureovernight and then diluted with EtOAc (70 mL). The organic layer waswashed with dilute HCl (30 mL), water (30 mL), and brine (30 mL), andthen dried over Na₂SO₄. The solids were filtered off and the filtrateconcentrated on a rotavap. The residue was purified on silica gel (5% to15% EtOAc in hexanes) to give the product (0.050 g) as a white solid.ESI [M+H⁺]=609.2.

EXAMPLE 186N-Benzyl-1-(3,5-dichloro-2-hydroxy-benzenesulfonyl)-N-(2-dimethylamino-ethyl)-pyrrolidine-2-carboxamide

To a solution of N-t-Boc-L-proline (2.0 g, 9.29 mmol) in anhydrous DMF(15 mL) were sequentially added N′-benzyl-N,N-dimethylethylendiamine(1.65 g, 9.29 mmol), EDC (2.31 g, 12.0 mmol), and HOBT (1.62 g, 12.0mmol). The reaction mixture was stirred at room temperature for 3 hbefore being poured into water (75.0 mL). The resulting solution wasextracted with ethyl acetate (50 mL), and the organic layer wasseparated and washed with 10% sodium bicarbonate (aq. 15 mL). Theorganic layer was dried over magnesium sulfate and concentrated Theresidue was treated with 4 N HCl in dioxin (10 mL), and the mixture wasstirred at room temperature. The reaction was completed after 20 min andthe crude reaction mixture was washed with saturated bicarbonate (aq.145 mL) (pH=9) and then extracted with ethyl acetate (50 mL). Theorganic layer was dried over MgSO₄, and then concentrated to give ayellow oil (1.5 g). To a solution of this oil (100.0 mg) in anhydrousTHF (4 mL) was added triethylamine (0.5 mL) and3,5-dichloro-2-hydroxybenzenesulfonyl chloride (91.0 mg, 0.36 mmol) inone portion. The reaction mixture was stirred at room temperature andthe reaction was monitored by TLC. The reaction was completed after 15min and water was added to the mixture. The resulting solution wasextracted with ethyl acetate and the organic layer was washed with 5%NaHCO₃ (10 mL). The organic layer was dried over MgSO₄ and thenconcentrated to give the crude product which was purified by silica gelchromatography using 3% methanol in ethyl acetate as the eluent. Thetitle compound was obtained as an off-white solid (135 mg). ESI[M+H⁺]=500.16.

The compounds of Examples 187-190 are prepared by the procedure ofExample 186.

physical Example structure name description M + H 186

N-benzyl-1-(3,5-dichloro-2-hydroxy-benzenesulfonyl)-N-(2-dimethylamino-ethyl)-pyrrolidine-2-carboxamideoff-white solid 500.16 187

ethyl3-benzenesulfonylamino-3-(1-ethyl-2-methyl-2,3-dihydro-1H-indol-5-yl)-propionate188

1-(3,4-dimethoxy-benzenesulfonyl)-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-1H-indole-6-carboxamidewhite solid 512.03 189

N-(1-(benzyl-thiophen-2-ylmethyl-aminocarbonyl)-ethyl)-4-methoxy-3-pyrrolidin-1-yl-benzamide190

N-(3-hydroxy-pyridin-2-yl)-4-methoxy-3-pyrrolidin-1-yl-benzamide beigesolid 314.36

EXAMPLE 1913-Benzenesulfonylamino-N-(2,4,6-trimethyl-3-pyrrolidin-1-yl-phenyl)-benzamide

The title compound was synthesized according to the protocol shown inScheme 2 using Example 165 and benzenesulfonyl chloride as the startingmaterials. It was obtained as a yellow solid ESI [M+H⁺]=464.25.

EXAMPLE 1923,5-Dichloro-N-(2-cyano-3-piperidin-1-yl-phenyl)-2-hydroxy-benzenesulfonamide

The title compound was synthesized according to the protocol shown inScheme 2 using 44 and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride asthe starting materials. It was obtained as an off-white solid ESI[M+H⁺]=423.97.

The CCR-9 antagonist compounds of the present invention may be preparedby the following general procedures:

Standard abbreviations include the following:

DMF, N,N-dimethylformamide

THF, Tetrahydrofuran,

TEA, Triethylamine,

DIPEA, N,N-Diisopropyl ethylamine

DMAP, 4-N,N-dimethylaminopyridine,

Pd₂(dba)₃, Tris(dibenzylideneacetone)dipalladium(0)

BINAP, (+/−)-2,2′-Bis(diphenylphosphino)-1-1′-binaphthyl

EXAMPLE 193 Preparation of Compounds of Scheme 1

Step One

Methyl 3-aminothiophene-2-carboxylate (3.14 g, 20 mmol) was dissolved inpyridine (10 mL) at room temperature. The flask was sealed with a septumand a nitrogen inlet. The solution was treated slowly with abenzenesulfonyl chloride (2.5 mL, 19.5 mmol). The reaction was followedby thin layer chromatography. The reaction was diluted with ethylacetate and washing with 2N HCl. The organic layer was washed withsaturated, aqueous sodium chloride solution and dried over sodiumsulfate. The solution was decanted and evaporated under reduced pressureto give 3-benzenesulfonylaminothiophene-2-carboxylic acid methyl ester(5.36 g, 90%), which was used without further purification.

Step Two

3-Benzenesulfonylaminothiophene-2-carboxylic acid methyl ester (1.5 g,5.0 mmol) was dissolved in acetonitrile (10 mL) and treated withaqueous, sodium hydroxide solution (2N, 7.5 mL, 3 equivalents) at roomtemperature. The solution was warmed to 50° C. and monitored by thinlayer chromatography. Upon completion of the reaction, the mixture wascooled and extracted once with diethyl ether. The ether layer was setaside. The aqueous layer was then acidified with aqueous HCl (2N,excess) before re-extracting twice with ethyl acetate. The combinedorganic layers were washed once with brine solution and dried overanhydrous sodium sulfate. The ethyl acetate was decanted and evaporatedunder reduced pressure to give of3-benzenesulfonylaminothiophene-2-carboxylic acid (1.34 g, 95%) as awhite powder.

Step Three

3-Benzenesulfonylaminothiophene-2-carboxylic acid (0.61 g, 2.15 mmol)was suspended in dichloromethane (8.6 mL). The resulting mixture wassequentially treated with N,N-dimethylformamide (1 drop), and, in twoportions, oxalyl chloride (0.42 mL, 4.8 mmol). After stirring briefly atroom temperature, the foaming subsided and the solution was refluxeduntil the reaction was complete. The mixture was concentrated todryness, re-dissolved in dichloromethane, and filtered through verysmall pad of course silica gel, eluting with dichloromethane. Uponconcentration of the eluent, the desired3-benzenesulfonylaminothiophene-2-carboxylic acid chloride was obtainedas a yellow solid (0.32 g, 49%), which was used without furtherpurification.

Step Four

To a solution of 2,4,6-trimethylaniline (70 mg, 0.518 mmol) indichloromethane (0.20 mL) and triethylamine (72 □L, 0.52 mmol) was added3-benzenesulfonylamnino-thiophene-2-carboxylic acid chloride (134 mg,0.444 mmol). The resulting mixture was allowed to stir overnight at roomtemperature under a nitrogen atmosphere. The reaction mixture wasapplied directly to silica gel, (9:1 hexane/ethyl acetate, gradient to4:1 hexane ethyl acetate). The compound was then precipitated fromhexanes and dichloromethane to give3-benzenesulfonylamino-thiophene-2-carboxylic acid(2,4,6-trimethylphenyl) amide as a white solid (0.028 g, 16%).

The following sulfonyl chlorides may be substituted for benzenesulfonylchloride of Step One:

-   4-Acetamidobenzenesulfonyl chloride-   4-Acetylbenzenesulfonyl chloride-   3-Acetylbenzenesulfonyl chloride-   2-Acetylbenzenesulfonyl chloride-   2-Biphenylsulfonyl chloride--   3-Biphenylsulfonyl chloride--   4-Biphenylsulfonyl chloride--   3,5-Bis(trifluoromethyl)benzenesulfonyl chloride-   4-tert-Butylbenzenesulfonyl chloride-   butanesulfonyl chloride-   2-Chlorobenzenesulfonyl chloride-   3-Chlorobenzenesulfonyl chloride-   4-Chlorobenzenesulfonyl chloride-   2-Cyanobenzenesulfonyl chloride-   3-(Chlorosulfonyl)benzoic acid-   5-Chloro-2-fluorobenzenesulfonyl chloride-   4-Chloro-2,5-dimethylbenzenesulfonyl chloride-   2-Chloro-4-(trifluoromethyl)benzenesulfonyl chloride-   2-Chloro-4-fluorobenzenesulfonyl chloride-   3-Chloro-4-fluorobenzenesulfonyl chloride-   3-Chloro-2-fluorobenzenesulfonyl chloride-   2-Chloro-6-methylbenzenesulfonyl chloride-   5-Chlorothiophene-2-sulfonyl chloride-   cyclopentanesulfonyl chloride-   cyclohexanesulfonyl chloride-   2,3-Dichlorobenzenesulfonyl chloride-   2,4-Dichlorobenzenesulfonyl chloride-   2,5-Dichlorobenzenesulfonyl chloride-   2,5-Dichlorothiophene-3-sulfonyl chloride-   2,5-Dimethoxybenzenesulfonyl chloride-   3,4-Dimethoxybenzenesulfonyl chloride-   2,6-Dichloro-4-(trifluoromethyl)benzenesulfonyl chloride-   2,6-Dichlorobenzenesulfonyl chloride-   2,6-Difluorobenzenesulfonyl chloride-   3,4-Dichlorobenzenesulfonyl chloride-   3,4-Difluorobenzenesulfonyl chloride-   3,5-Dichloro-2-hydroxybenzenesulfonyl chloride-   3,5-Dichlorobenzenesulfonyl chloride-   3,5-Difluorobenzenesulfonyl chloride-   4-Ethylbenzenesulfonyl chloride-   Ethanesulfonyl chloride-   2-Fluorobenzenesulfonyl chloride-   3-Fluorobenzenesulfonyl chloride-   4-Fluorobenzenesulfonyl chloride-   4-Fluoro-2-methylbenzenesulfonyl chloride-   3-Fluoro-4-methylbenzenesulfonyl chloride-   3-Fluoro-4-methylbenzenesulfonyl chloride-   5-Fluoro-2-methylbenzenesulfonyl chloride-   Methanesulfonyl chloride-   2-Methoxybenzenesulfonyl chloride-   3-Methoxybenzenesulfonyl chloride-   4-Methoxybenzenesulfonyl chloride-   Methanesulfonyl chloride-   2-Methoxy-4-methylbenzenesulfonyl chloride-   4-Phenoxybenzenesulfonyl chloride-   Propanesulfonyl chloride-   Quinoline-8-sulfonyl chloride-   2-(Trifluoromethyl)benzenesulfonyl chloride-   3-(Trifluoromethyl)benzenesulfonyl chloride-   4-(Trifluoromethyl)benzenesulfonyl chloride-   2-(Trifluoromethoxy)benzenesulfonyl chloride-   3-(Trifluoromethoxy)benzenesulfonyl chloride-   4-(Trifluoromethoxy)benzenesulfonyl chloride-   m-Toluenesulfonyl chloride-   p-Toluenesulfonyl chloride-   o-toluenesulfonyl chloride-   2,4,5-Trichlorobenzenesulfonyl chloride-   2,4,6-Triisopropylbenzenesulfonyl chloride-   2,3,4-Trifluorobenzenesulfonyl chloride

It is also envisioned that the following anilines and amines may besubstituted for 2,4,6-trimethylaniline of Step Four:

-   2,4,6-trimethyl-3-piperidinoaniline-   2,6-dimethyl-3-piperidinoaniline-   2,4-dimethyl-3-piperidinoaniline-   4,6-dimethyl-3-piperidinoaniline-   2,6-dimethyl-3-pyrrolidinoaniline-   2,4-dimethyl-3-pyrrolidinoaniline-   4,6-dimethyl-3-pyrrolidinoaniline-   2,4,6-trimnethyl-3-(1-imidazolyl)aniline-   2,4,6-trimethyl-3-(1-pyrrolidyl)aniline-   2,6-dimethyl-3-(1-pyrrolidyl)aniline-   2,4-dimethyl-3-(1-pyrrolidyl)aniline-   4,6-dimethyl-3-(1-pyrrolidyl)aniline-   2,4,6-trimethyl-3-cyclopentylaniline-   2,6-dimethyl-3-cyclopentylaniline-   2,4-dimethyl-3-cyclopentylaniline-   4,6-dimethyl-3-cyclopentylaniline-   2,4,6-trimethyl-3-cyclohexylaniline-   2,6-dimethyl-3-cyclohexylaniline-   2,4-dimethyl-3-cyclohexylaniline-   4,6-dimethyl-3-cyclohexylaniline-   2,4,6-trimethyl-3-(N,N-dimethylamino)aniline-   2,6-dimethyl-3-(N,N-dimethylamino)aniline-   2,4-dimethyl-3-(N,N-dimethylamino)aniline-   4,6-dimethyl-3-(N,N-dimethylamino)aniline-   Morpholine-   Piperazine-   Piperidine-   Pyrrolidine

EXAMPLE 194 Preparation of Compounds of Scheme 2

Step One

To a solution of 3-bromonitrobenzene (2.02 g, 10 mmol) in toluene (33mL) and pyrrolidine (1.0 mL, 12 mmol) was added sodium t-butoxide (1.92g, 20 mmol) and the solution was deoxygenated by passing a nitrogenthrough the solution at room temperature for 15 minutes. BINAP andtris(dibenzylideneacetone)dipalladium(0) complex were subsequently addedas a solid and the nitrogen bubbling was continued for an additional 5minutes. The mixture was heated at 100° C. overnight. The reactionmixture was then cooled and partitioned between water and ethyl acetate.The organic layer was washed once with brine solution and dried overanhydrous sodium sulfate. The ethyl acetate was decanted and evaporatedunder reduced pressure to give the desired 1-(3-nitrophenyl)pyrrolidineas a red oil (1.5 g, 79%).

Alternatively, under these conditions, 3-bromo-2,4,6-trimethylanilinemay be substituted for 3-bromotoluene to prepare the corresponding3-pyrrolidino-2,4,6-trimethylaniline, except that the pyrrolidine isincreased to 5 equivalents.

Step Two

To a solution of 1-(3-nitrophenyl)pyrrolidine (1.5 g, 7.8 mmol) inmethanol (25 mL) was added Pd/C (10%, Degusa type E101, 50% water, 1 g)and ammonium formate (0.96 g, 15 mmol). The resulting suspension washeated at reflux until the reaction was complete. The mixture wasfiltered through celite and concentrated under reduced pressure filteredthrough course silica gel with ethyl acetate to give the desired product3-(1-pyrrolidino)aniline (0.65 g, 79%).

EXAMPLE 195 Preparation of Compounds of Scheme 3

Step One

To a solution of an aniline (1.02 g, 10.9 mmol, 1.1 equivalents)dissolved in dry THF (35 mL) and triethylamine (1.53 mL, 1.1equivalents) at room temperature, sealed with a septum and a nitrogeninlet, was added 2-carbomethoxythiophene-3-sulfonyl chloride (2.5 g, 9.9mmol, 95% purity). The reaction mixture was stirred at room temperatureover night. Upon completion, the reaction will be extracted by dilutingwith ethyl acetate and washing with aqueous HCl (2N), water andsaturated, aqueous sodium chloride solution. The organic layer was driedover sodium sulfate. The solution will be decanted and evaporated underreduced pressure to give the desired3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester (2.6 g, 88%).

Step Two

The Sulfonamide of Step One, 3-phenylsulfamoylthiophene-2-carboxylicacid methyl ester, was dissolved in dry dichloromethane andN,N-diisopropyl ethylamine. The resulting mixture was chilled to 0° C.prior to the addition of bromomethyl methyl ether. The reaction mixturewas stirred over night at room temperature. The mixture was partitionedbetween dichloromethane and aqueous HCl (2N). The organic layer willthen be washed one time with saturated sodium chloride solution anddried over sodium sulfate, followed by concentration to dryness underreduced pressure to give the desired product,3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methylester (3 g, quantitative).

Step Three

To a homogenous mixture of3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methylester (3 g, 8.75 mmol) in methanol and water was added aqueous, sodiumhydroxide solution (2N, excess) at room temperature. Upon completion ofthe reaction, the mixture was cooled and extracted once with diethylether. The aqueous layer will then acidified with aqueous, HCl (2N,excess) before re-extracting twice with ethyl acetate. The organic layerwas washed once with brine solution and dried over anhydrous sodiumsulfate. The ethyl acetate solution was decanted and evaporated underreduced pressure to give the desired3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid (2.2 g,79%).

Step Four

The 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid ofstep three (0.722, 2.2 mmol) was suspended in dichloromethane (5 mL),followed by sequentially treating with pyridine (1 drop) and chilled to0° C. The solution was then treated with oxalyl chloride (2.43 mL, 2M indichloromethane) before refluxing for 1 hour. The mixture was cooled toroom temperature and concentrated to dryness under reduced pressure. Theresidue was re-dissolved in tetrahydrofuran (5 mL) and added to a cold(0° C.) solution of 3-pyrrolidino-2,4,6-trimethylaniline (0.250 g, 1.2mmol) in tetrahydrofuran (4 mL), triethylamine(0.36 mL 2.6 mmol) and4-dimethylaminopyridine (0.027 g, 10 mol %). The reaction mixture wasallowed to stir at room temperature over night. The material waspurified by normal phase (SiO₂) chromatography by eluting with 3:1hexanes:ethyl acetate to give3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid) (107mg, 15%).

Step Five

3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid (107mg, 0.331 mmol) of the previous step was dissolved in methanol andtreated with a concentrated HCl (9 mL). The reaction mixture was heatedto 70° C. for 2.5 hours, cooled and poured onto ice water. The pH wasadjusted to 3-4, and the aqueous mixture was extracted with ethylacetate. The organic layer was washed with saturated sodium chloridesolution and dried over sodium sulfate before concentrating to drynessunder reduced pressure to give the desired product such as3-phenylsulfamoylthiophene-carboxylic acid(2,4,6-trimethylphenyl) amide(40 mg, 26%).

1. A compound of the formula:

where E is S; D is O or S; Z is NR^(13a), where R^(13a) is H or loweralkyl; A is NR¹⁷ or SO₂, where R¹⁷ is H, alkyl or aryl when A is NR¹⁷, Bis SO₂; when A is SO₂, B is NR¹⁹, where R¹⁹ is H alkyl or aryl; R¹⁴ isphenyl; R¹³ is phenyl; and R¹⁵ and R¹⁶ are independently H, alkyl, aryl,heteroaryl, halogen, hydroxy, alkoxy or NR₂ ²¹, where R²¹ is H, alkyl,aryl or heteroaryl, and the pharmaceutically acceptable salts thereof,wherein the alkyl, heteroaryl and alkoxy groups are unsubstituted orsubstituted with one or more groups selected from alcohol, ether, ester,amide, sulfone, sulfide, hydroxyl, nitro, cyano, carboxy, amine,heteroatom, lower alkyl, lower alkoxy, lower alkoxycarbonyl,alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl,alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy,carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,alkylbeterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl; R¹⁴ is substituted with unsubstituted orsubstituted with one or more groups selected from alcohol, ether, ester,amide, sulfone, sulfide, hydroxyl, nitro, cyano, carboxy, amine,heteroatom, lower alkyl, lower alkoxy, lower alkoxycarbonyl,alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl,alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy,carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,alkylbeterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl; and R¹³ is substituted with lower alkyl andheterocyclyl.
 2. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier or excipient.
 3. Acompound selected from a group consisting of:


4. A pharmaceutical composition comprising a compound of claim 3 and apharmaceutically acceptable carrier or excipient.